Use of small molecule radioligands to discover inhibitors of amyloid-beta peptide production and for diagnostic imaging

a technology of amyloidbeta peptide and small molecule radioligand, which is applied in the direction of radioactive preparation carriers, in-vivo testing preparations, therapy, etc., can solve the problems of major present and future health problems

Inactive Publication Date: 2005-06-16
ZACZEK ROBERT +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0022] One object of the present invention is to provide a method for diagnosing a neurological disease involving APP processing and/or the production of beta-amyloid production within a mammalian body comprising: a) administering a diagnostically effective amount of a radiopharmaceutical inhibitor of APP processing and/or the production of beta-amyloid production; and b) imaging the area of the patient wherein the disease is located.
[0023] It is another object of the present invention to provide a method for diagnosising a neurological disease involving APP processing and/or the production of beta-amyloid production within a mammalian body comprising: a) administering a diagnostically effective amount of an ultrasoun...

Problems solved by technology

AD has been observed in all races and ethnic groups w...

Method used

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  • Use of small molecule radioligands to discover inhibitors of amyloid-beta peptide production and for diagnostic imaging
  • Use of small molecule radioligands to discover inhibitors of amyloid-beta peptide production and for diagnostic imaging
  • Use of small molecule radioligands to discover inhibitors of amyloid-beta peptide production and for diagnostic imaging

Examples

Experimental program
Comparison scheme
Effect test

example 1

(2R,3S) N1-[(3S)-hexahydro-1-(3,3-diphenylpropyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

[0716]

[0717] Step (1a): Di-tert-butyldicarbonate (10.2 g, 46.7 mmoles) was added portion wise to a solution of L-(−)-α-amino-ε-caprolactam (5.0 g, 39.0 mmoles) in dimethyl sulfoxide (30 mL). After 5 h at rt, the reaction was partitioned between water (100 mL) and ethyl acetate. The combined organic extracts were washed successively with 1 M HCl (50 mL), brine, and dried (MgSO4) and concentrated in vacuo. The residue was recrystallized in 1:1 v / v ether-hexanes, two crops yielded the desired product (6.26 g, 70%) as white solid. MS (M+H-BOC)+=129.

[0718] Step (1b): Triphenylphosphine (3.0 g, 11.4 mmoles) and carbon tetrabromide (3.75 g, 11.7 mmoles) were added successively to a cooled (0° C.) solution of 3,3-biphenyl-1-propanol (1.5 mL, 7.5 mmoles) in dichloromethane (20 mL). After 1.5 hours at rt, the mixture was concentrated in vacuo. The residue was puri...

example 2

(2R,3S) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

[0724]

[0725] Step (2a): Triphenylphosphine (3.40 g, 13.0 mmoles) and carbontetrabromide (4.20 g, 13.0 mmoles) were added successively to a solution of m-phenoxybenzyl alcohol (1.5 mL, 8.6 mmoles). After 4 h at rt the mixture was concentrated and was purified by silica gel column (hexanes, then ethyl acetate:hexanes, 5:95) to give the desired bromide (1.3 g, 57%) as a yellow oil. MS (M-Br)+=183.

[0726] Step (2b): A 1 M solution of lithium bis(trimethylsilyl)amide was added dropwise to a solution of compound of Step (1a) (0.3 g, 1.31 mmoles) in tetrahydrofuran (5 mL) at −78° C. After 30 minutes a solution of compound of Step (2a) (0.43 g, 1.63 mmoles) in tetrahydrofuran (4 mL) was added to the mixture dropwise. The reaction was allowed to come to ambient temperature, stirred for 16 h, then partitioned between water and ethyl acetate. The combined organic extra...

example 3

(2R,3S) N1-[(3S)-hexahydro-1-(phenyl)-2-oxo-1H-azepin-3-yl]-N-4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

[0731]

[0732] Step (3a): Triethylamine (1.5 mL, 10.8 mmoles), copper (II) acetate (0.95 g, 5.2 mmoles) and phenylboric acid (1.6 g, 13.1 mmoles) were added successively to a solution of compound of Step (1a) (1.0 g, 4.4 mmoles) in dichloromethane (20 mL). After 2.5 h at rt, more phenylboric acid (0.5 g, 4.1 mmoles) was added to the mixture. After an additional 3 hours at rt more phenylboric acid (0.5 g, 4.1 mmoles) was added to the mixture. After 65 h at rt, the mixture was filtered over celite. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography (ethyl acetate:hexanes, 5:95 then 15:85) to give the desired product (250 mg, 19%). MS (M-Ot-Bu)+=231.

[0733] Step (3b): Following a procedure analogous to the preparation of compound of Step (2c), but using compound of Step (3a) (250 mg, 0.82 mmoles), the amine (300 mg, 99%) was ...

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Abstract

This invention relates to a method of using radiolabelled and/or radiopharmaceutical small molecule inhibitors of beta-amyloid peptide production for the diagnosis of neurological and other disorders involving APP processing and beta-amyloid production. Furthermore, radiolabelled small molecule inhibitors identified by the methods of the present invention would be useful in the diagnosis of neurological disorders, such as Alzheimer's disease, which involve elevated levels of Aβ peptides.

Description

RELATED PRIOR ART [0001] This application is a continuation of Ser. No. 09 / 859,261, filed May 17, 2001(allowed), which claims priority of provisional application No. 60 / 204,685, filed May 17, 2000, which disclosure is incorporated entirely herein by reference.FIELD OF THE INVENTION [0002] This invention relates to a method of using radiolabelled and / or radiopharmaceutical small molecule inhibitors of beta-amyloid peptide production for the diagnosis of neurological and other disorders involving APP processing and beta-amyloid production. Furthermore, radiolabelled small molecule inhibitors identified by the methods of the present invention would be useful in the diagnosis of neurological disorders, such as Alzheimer's disease, which involve elevated levels of A□ peptides. BACKGROUND OF THE INVENTION [0003] Alzheimer's disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, temporal and local orientation, cognition, reasoning, judgment an...

Claims

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Application Information

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IPC IPC(8): A61K51/08
CPCA61K51/0468
Inventor ZACZEK, ROBERTOLSON, RICHARD E.SEIFFERT, DIETMAR A.THOMPSON, LORIN A.
Owner ZACZEK ROBERT
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